Kalaba, M. and Kosutic, J. and Godman, Brian and Radonjic, V. and
Vujic, A. and Jankovic, S. and Srebro, D. and Z., Kalaba and Stojanovic,
R. and Prostran, M. (2017) Experience with developing antibiotic
stewardship programmes in Serbia : potential model for other Balkan
countries? Journal of Comparative Effectiveness Research. ISSN
2042-6313 (In Press) ,
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Experience with developing antibiotic stewardship programmes in Serbia; potential model
for other Balkan countries?
Kalaba M
1, Kosutic J
2,3, *Godman B
4,5,6, Radonjic V
7, Vujic A
8, Jankovic S
8, Srebro D
3, Kalaba
Z
9, Stojanovic R
3,10, Prostran M
3,101
Primary Healthcare Centre “Zemun“, Šilerova 46, Belgrade, Serbia Email:
2
The Institute for Medical Care of Mother and Child of Serbia "Dr Vukan Cupic", Radoja
Dakića, Belgrade, Serbia,
Email:
3
School of Medicine University of Belgrade, Serbia. Email: [email protected]
4Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow,
UK. Email:
5
Division of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital
Huddinge, SE-141 86, Stockholm, Sweden. Email:
6
Health Economics Centre, Liverpool University Management School, Liverpool, United
Kingdom. Email: [email protected]
7
Medicine and Medical Device Agency of Serbia, Belgrade, Serbia. Email:
8
Clinical Center Kragujevac, Zmaj Jovina street 30, Kragujevac, Serbia. Email:
[email protected]
,
9
Children Hospital for Pulmonary Diseases and Tuberculosis at University Hospital Center
“Dr
Dragisa Misovic
”, Belgrade, Email:
10
Clinical Pharmacology Unit, Clinical Center Serbia. Emails:
,
*Author for correspondence: Brian Godman, Division of Clinical Pharmacology, Karolinska
Institute, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden. Email:
; Telephone: +46 8 58581068. Fax: +46 8 59581070 and Strathclyde Institute
of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United
Kingdom. Email:
.
(Accepted for publication in Journal of Comparative Effectiveness Research
–
please keep
CONFIDENTIAL)
ABSTRACT
Introduction
: Antimicrobial resistance (AMR) and inappropriate use of antibiotics in children
are important issues. Consequently, there is a need to develop comprehensive stewardship
programmes even in hospitals with limited resources
starting with children’s hospital
s.
Method
:
Retrospective observational analysis of antimicrobial utilization and resistance patterns over five
years in a tertiary care children
’s
hospital in Serbia.
Results
: Cumulative AMR decreased but
were still high, with high cumulative resistance rates among the most widely used antibiotics in
the hospital. Total antibiotic use decreased from 2010 to 2014 although there was still high
prescribing of reserved antibiotics.
Conclusion:
Concerns with inappropriate use, and high
resistance rates, among some antibiotics used in the hospital are being used to develop guidance
on future antibiotic use in this hospital, building on the recently introduced antibiotic stewardship
programme, as well as encourage other hospitals in Serbia to review their policies.
Key words: Serbia, antibiotic resistance, antibiotic utilisation, children, hospitals, low-resources,
stewardship programmes
INTRODUCTION
There are concerns with increasing resistance to antibiotics through their inappropriate use,
leading to increased morbidity, mortality and costs [1-5]. The costs of antibiotic resistance in
Europe were estimated at €1.5billion in 2007, now reaching €9bill
ion per year or higher [6, 7],
with costs also increasing with the use of newer more expensive antibiotics to treat resistant
organisms [2, 8]. As a result, the monitoring of antimicrobial resistance (AMR), antibacterial use
and the establishment of infection control programs, including the development of antibiotic
stewardship programmes in hospitals, are seen as increasingly necessary to reduce resistance
development and conserve existing antibiotics [9-15]. As part of this, antibiotic prescribing in
children is of primary concern to reduce future morbidity and mortality. This includes both
access to antibiotics, which can be a concern in some countries, as well as appropriate use [2, 3,
7].
In Serbia, antimicrobial use policies within hospitals are principally based on administrative
measures and restrictions. In 2005, the concept of reserving antibiotics was implemented within
the reimbursed hospital drug list, List B. This has resulted in regulations regarding their use
including countersigning by specialists, and an evaluation of the microbiological outcomes [16,
17]. Under exceptional circumstances, hospitals can use an antibiotic which is not on the positive
list [18]. Currently, restricted antibiotics include the carbapenems, linezolid, vancomycin,
piperacillin-tazobactam, teicoplanin, colistin and ceftriaxone. In addition in 2013, the Ministry of
Health requested that every hospital in Serbia should establish an antibiotic committee to
instigate AMR monitoring and reporting as well as give professional advice for the rational use
of antibiotics [19]. However, there were limited resources to implement such measures.
Despite these initiatives, data regarding antibiotic use and AMR patterns among children in
hospitals in Serbia is currently very limited. This is not helped by the fact that antibiotic
prescriptions and microbiology test results are often recorded on separate pieces of paper by
different departments. As a result, making correlations between the two data sets challenging.
This will potentially compromise the implementation of activities such as surveillance of
antibiotic utilization and/ or AMR patterns.
Consequently, we sought to combine these two datasets within a leading children’s hospital in
Serbia to guide future empiric use as part of antimicrobial stewardship programs. Our
assumption was that if we found concerns in a leading children’s hospital in Serbia, there will be
a high likelihood of similar concerns among other hospitals in Serbia where children are being
treated as well as more widely within Serbia.
MATERIALS AND METHODS
A retrospective drug utilisation and surveillance study was conducted among the paediatric and
paediatric surgery clinics (125 beds) of a tertiary care institution in Serbia, the Clinical Centre
Kragujevac hospital, which overall has 1274 beds. The number of beds available for children
(patients aged 0-18 years) did not significantly change during the study period, with the number
of bed days oscillating between 28576 and 36171 per year in the paediatric wards.
In the first part of the study, we undertook an analysis combining antimicrobial utilisation data
with cumulative resistance in 2010 vs 2014.
Antibiotic utilisation data was measured using the ATC DDD methodology, with DDDs
typically accepted for recording medicine use for comparative purposes [20-24]. We are aware
that DDDs are normally assigned based on their use in adults, and for medicines approved for
use in children, dose recommendations will differ based on
children’s
age and body weight. In
addition, many medicines used in children are typically not approved for such use, and
documentation regarding dosing regimens are generally unavailable. Consequently, the WHO
International Working Group for Drug Statistics Methodology concluded that paediatric DDDs
are impossible to assign, and prescribed daily dosages (PDDs) and indications in paediatric
population should be used if available [25]. However, if this is difficult, the Working Group
suggested DDDs should be used as a measuring tool for overall comparisons [25].
Antibiotic dispensing data were collected from the hospital pharmacy on all antibiotics
prescribed for systemic use among children from 2010-2014. In order to concentrate on the most
prescribed antibiotics, the data on their utilization was limited to those antibiotics which
comprised 90% of total utilization expressed in DDDs/100 patient days [23,26,27]. At the same
time, we followed the percentages of bacterial isolates resistant and susceptible to the same
antibiotics that were used in the study site. Utilization and resistance rates were combined.
Cumulative resistance rates were calculated for those microbes naturally susceptible to each
antibiotic from those antibiotics comprising 90% of total antibiotic utilisation as a percentage of
resistance, intermediate or susceptible strains from the total number of strains analysed. Resistant
and intermediate strain data were subsequently combined. . This is part of ongoing antimicrobial
stewardship programmes in the hospital.
We are aware that antibiotic stewardship programs do differ in their content from hospital to
hospital, and from country to country, to reduce infections and colonisation with
antibiotic-resistant bacteria within hospitals [15,28,29]. We are also aware that there is limited data
available on their implementation and effectiveness among paediatric patients [30]. In the
Clinical Center Kragujevac, antibiotic stewardship (AS) was composed of the following
elements: (i) establishing a drug and therapeutics committee (DTC), (ii) issuing antibiotic
prescribing policies and hospital formularies via the DTC, (iii) biannual analysis of resistance
patterns among the isolates from the central Intensive Care Unit and its distribution to all
clinicians, (jv) pre-authorization of reserve antibiotics dispensing by a clinical pharmacology
specialist, (v) issuing local guidelines for antibiotic prophylaxis and empiric treatment and
consulting clinical pharmacologists and infectious diseases specialists when prescribing
antibiotics to complex patients. The AS was fully implemented in this hospital at the beginning
of 2014, and is ongoing.
Data on antimicrobial resistance were obtained from hospital microbiological laboratory. This
included more than 90,000 uniform Excel files from 2010 to 2014 containing information for
instance regarding the clinic/ ward where the specimens were collected and in which material,
e.g. sputum, blood or liquor, which bacteria were isolated, what antibiotics were used to test
potential bacteria resistance and what were the results. Using Excel macros, data involving
children were extracted for each year. The data were subsequently filtered to improve the
understanding in tables and graphs. Duplicate samples with the same isolates from the same
patients were taken into account as one sample.
We included only species with at least ≥30 isolates tested. Under certain circu
mstances, when we
did not have ≥30 isolates, we combined the isolates form two consecutive years into the
calculations [27]. All sources of potential microbes, including pus, sputum, wounds, blood, and
urine, were analyzed together since we wished to represent the total volume of resistant
pathogens circulating in the hospital. Microbiology reports define resistant, intermediate or
sensitive strains according to Clinical and Laboratory Standard Institute standards [31].
Antimicrobial susceptibility systems employed by the microbiology department have not
changed through the years.
The costs per DDD were also calculated to help with future guidance. Cost data was recorded in
local currency (RSD) to avoid problems with currency conversions. This included developments
in the procurement system, including centralised procurement, to help reduce costs [32].
In the second part of the study, we looked at antimicrobial resistance patterns in more detail for
five consecutive years to determine specific cumulative resistance and utilisation rates for the
predominant bacterial population to provide future guidance. For these microbes, cumulative
resistance rates were calculated for the most used antibiotics from the antibiotic panel used in the
sensitivity tests with the same methodology described above.
Data from clinical and surgical units included in the study are provided in one group as the first
step of introducing a new surveillance systemin hospital settings with limited resources. This
methodology can be further modified by the type of medical specialty (medical vs surgical, ICU
and non-ICU) since the nature of any surveillance system is to disentangle the epidemiology of
antibiotic use and define areas at risk of antibiotic misuse.
No ethical approval was sought since this study collected anonymised aggregated data. This is in
line with other studies employing similar methodologies [22, 33-35], and is the current situation
in Serbia.
RESULTS
Antibiotic utilisation data
Figure 1 documents the utilisation and resistance profile
for antibiotics for systemic use (ATC
J01) in the paediatric and paediatric surgery clinics of Clinical Center Kragujevac in 2010.
Figure 1
–
Drug utilisation 90%-cumulative resistance profile in 2010
In 2010, antibiotics outside DU90% included ampicillin, benzylpenicillin, fenoximetilpenicillin,
benzylpenicillin procaine, chloramphenicol, cefazolin, cefuroxime, cefprozil, cefepime,
imipenem/cilastatin, clarythromycin, clindamycin, gentamicyn, vancomycin, teicoplanin, colistin
and metronidazole. Table 1S (Supplementary material) documents
the 15 antibiotics ranked in
order of number DDDs corresponding to 90% of their use in 2010 as well as percentage
resistance.
Figure 2 documents antibiotics for systemic use (ATC J01) as well as resistance profiles in
paediatric and paediatric surgery clinics of Clinical Center Kragujevac in 2014.
Figure 2
–
Drug utilisation 90%-cumulative resistance profile in 2014
In 2014 antibiotics outside DU90% included chloramphenicol, ampicillin/sulbactam,
piperacillin/tazobactam, cefazolin, cefprozil, ceftazidime, imipenem/cilastatin,erythromycin,
clindamycin, gentamicyn, ofloxacyn, ciprophloxacyne, vancomycin, teicoplanin, colistin and
metronidazole.
Table 2S (Supplementary material)
documents the 15 antibiotics ranked in order
of number DDDs corresponding to 90% of the use in 2014
.
From the antibiotic DU90% profile for 2010 versus 2014, total antimicrobial use among children
in the hospital was 49.4 and 27.8 DDDs/100 bed days in 2010 versus 2014 (Tables 1S and 2S).
There were limited changes in the patterns of antibiotic use comparing 2010 with 2014. The
utilisation of reserve antibiotics from the reimbursement drug list was approximately 30% of the
total consumption within the DU90% segment, with high utilisation of ceftriaxone and low
utilisation of the other restricted antibiotics. Cumulative resistance rates generally decreased with
a slight increase of resistance to azithromycin (37.5% to 44.1%, 2010 vs. 2014, calculated by
dividing the number of resistant isolates by the total number of isolates). However, there was
high cumulative resistance to benzyl penicillin, amoxicillin and ampicillin as the antibiotic panel
used in sensitivity tests for S.aureus, the most common isolated bacteria, included these
antibiotics and almost all S.aureus tested were 100% resistant. No data on resistance patterns
were available for 4 of the 15 most commonly used antibiotics in 2014, while all were available
in 2010. These were cefixime, tobramycin, clarythromicin, and TMP/SMX.
Finally, the total
costs per DDD typically decreased during the study period.
Specific cumulative resistance and utilisation rates for predominant bacterial population
The number of the assays performed for the paediatric and paediatric surgery clinics was
comparable across the years, e.g. 4516 in 2010, 5268 in 2011, 4441 in 2012, 5217 in 2013 and
6871 in 2014.
The most identified isolated organisms in the paediatric and paediatric surgery clinics in Clinical
Center Kragujevac in 2014 were Staphylococcus aureus (36 %), Streptococcus pneumoniae
(20%) and Escherichia coli (13 %).
As methicillin resistance is CLSI-recommended surrogate for all beta lactams, we report just the
extent of methicillin resistant S. aureus [MRSA]. This reflected a general downward trend
from13.3% in 2010, to 3.8% in 2011, 0%in 2012, 6.7% in 2013, and 0.5% in 2014. Oxacillin is
currently not available in Serbia, just cloxacillin. However, the antibiotic panel used in
sensitivity tests for S.aures does not contain routine testing for cloxacillin. In addition,
cefpodoxime is not currently tested, with cefpodoxime known to have good activity among
major respiratory pathogens [36]
Figures 3 to 5 provide further details of the most common bacteria and the most common
antimicrobial resistance patterns. S. pneumoniae isolates used to create the antibiogram reflected
complicated and refractory infections since S. pneumoniae is not routinely cultured in
uncomplicated otitis media or pneumonia (Figure 3).
The percentage of isolates that conferred resistance to amoxicillin and amoxicillin/clavulanic
acid decreased from 30% in 2010 to 20% in 2014, and for ampicillin from 17% to 15%,
respectively. The percentage of isolates that conferred resistance to ceftriaxone and cefotaxime
increased to 13% and 15% in 2014 from 3% in 2010, respectively (Figure 3).
Regarding the most used antimicrobials tested, the proportion of erythromycin resistance varied
from 40% in 2010/2011 to 51% in 2014. Erythromycin susceptibility predicts azythromicin
susceptibility to S. pneumoniae. Clindamicin resistance varied 55% in 2010/2011 to 59% in
2014. All isolates with exception of one were susceptible to vancomycin in 2014 (0.5%).
Overall, 18% of S. pneumoniae at KC Kragujevac were resistant to penicillins.
According to CLSI recommended standards, CNS (central nervous system) breakpoints were
used for S. pneumoniae isolated from cerebrospinal fluid. During the study period, there were
three isolates and all were susceptible to ceftriaxone and one was resistant to penicillin.
Resistance to azythromicin was high throughout the study period (Figure 3). However, there is
no obvious association between the extent of azythromicin use and antibiotic resistance patterns
for S.pneumoniae.
Figure 4 shows the trend in resistance rate of E.coli to amikacin, amoxicillin/clavulanic acid,
TMP/SMX, cephtriaxone, ceftazidime, cefptaxime, cefalexin and meropenem. The results of
resistance rates for other tested antimicrobials in 2014 were 66% for ampicillin, 55% for
gentamicin, 52% for cefuroxime, 15% for cefepime, 7% ofloxacin, 5% nitrofurantoin and 0% for
imipenem and ertapeneme.
Figure 4. Antibiotic resistance patterns for Escherishia coli from 2010 to 2014 for antibiotics in
DU90% utilisation segment
ESBL-rates were estimated based on susceptibility to third-generation cephalosporins, such as
ceftazidime. The rate of ESBL-producing E.coli did not appreciably change during the study
period although there appeared to be a downward trend, i.e. 30% in 2010 and 28% in 2014
respectively.
Cefazoline is a first-generation parenteral cephalosporin and an important choice for the
treatment of acute UTI; however, its susceptibility is currently not routinely tested in the
hospital. However even for the cephalosporins that are routinely used in susceptibility tests, it is
not possible to make a straightforward decision whether their use was justified and therefore
whether they contributed to the observed resistance patterns. For example, without an insight in
diagnoses of the patients we could not decide about relation between ceftriaxone and resistance
rate shown in the Figure 5.
Figure 5. Trend analysis of ceftriaxone utilisation and resistance pattern for E.coli
Cost data
The total costs per DDD typically decreased during the study period (Tables 1S and 2S). For
example, the cost of ceftriaxone fell from 856 RSD/DDD in 2010 to 128 RSD/DDD in 2014,
meropenem from 4475 in 2010 to 1970 RSD/DDD in 2014, and cefixime from 193 in 2010 to
134 RSD/DDD in 2014 (Table 1).
Table 1
–
Cost/ DDD (in RSD) of antibiotics used among children in 2014.
DISCUSSION
Developing effective antibiotic policies in hospitals depends on the surveillance of current
resistance patterns, coupled with an understanding of current antibiotic utilization patterns, to
guide empiric use whilst sensitivity analyses are being undertaken. Hence, it should become
mandatory for hospitals to establish efficient surveillance systems along with monitoring current
antibiotic utilization to improve their appropriate use. This can be helped by instigating measures
such as the WHONET Software programme to monitor local resistance patterns; however, we
believe only one hospital in Serbia is currently using this programme [37].
From the antibiotic DU90% profile in 2010 vs, 2014, we can conclude that the cumulative
antimicrobial resistance is similar and relatively high (Figures 1 and 2 as well as Tables 1S and
2S), with high cumulative resistance rates among the most widely used antibiotics from 2010.
Overall, total antibiotic use decreased appreciably from 2010 to 2014 (Tables 1S and 2S);
however, there was high prescribing of the reserved antibiotic ceftriaxone. In addition, sensitivity
tests were not available for 4 of the 15 most commonly used antibiotics in 2014, pointing to a
lack of integration between microbiology and routine clinical care in the hospital. We will now
be reviewing this within the hospital to develop policies to improve future prescribing, and this
will be part of future studies. This can also act as an exemplar for other hospitals in Serbia to
improve future antibiotic prescribing.
One of the main findings of this study is the high resistance of S.pneumoniae to azythromicin
(Figure 3). This maybe because there has been high total antibiotic consumption in Serbia versus
other European countries in recent years [38]. In addition, antibiotic use among children in
primary care in Serbia has been extremely high, with frequent prescribing for indications with
little or no benefit from antibiotics such as upper respiratory tract infections [27]. This is
important since previous antibiotic exposure in primary care is related to high antibiotic
resistance in hospitals [39].
The debate continues in literature with regard to the impact of macrolide resistance on the
outcome of pneumococcal pneumonia. Antibiotic resistant strains increase the severity of illness
and make it more difficult to treat these infections effectively. Several cases of macrolide
treatment failure have been documented in the literature [40, 41], and with high levels of
macrolide resistance in this child
ren’s hospital, we believe these antibiotics should not be
routinely used as empiric therapy of S. pneumoniae whilst AMR rates remain high. Probable
reasons for the increase in resistance rate of azithromycin and amoxicillin in 2014, despite a
decrease in their intra-hospital use, is the extensive and unjustified prescribing of these
antibiotics in primary care. On the other hand, the antibiotics used only in hospitals such as
ceftriaxone had decreased both in usage and resistance rates. The main promoter of resistance to
antibiotics is likely inappropriate use of these antibiotics in ambulatory care especially for wrong
indications, which include potential viral infections, and this should be placed in focus in future
interventions within the healthcare system in Serbia and other countries. A reasonable alternative
to macrolides may be levofloxacin, which is already being used for the treatment of community
acquired pneumonia (CAP) in children in clinical trials [42, 43]. Although quinolones may have
adverse effects on the cartilage of great joints in children, recent studies with long-term
follow-up showed that this risk was overestimated and its use in hospitalized children with such serious
infection as CAP is justified [44]. Consequently, we have begun implementing this
recommendati
on in this children’s hospital,
alongside educational and other measures, to reduce
inappropriate macrolide use, and will be following this up in future studies to further guide
prescribing in this and other similar hospitals in Serbia.
Additionally, the Ministry of Health in Serbia is now planning to introduce in a national
immunization programme - the pneumococcal conjugate vaccine - in all infants and young
children. This may also be critical in reducing nasopharyngeal carriage and limit the
dissemination of drug-resistant strains [45-47]. We will also be monitoring this impact in the
future.
Rhamos et al. showed that the prevalence of resistance is country specific and reflects
differences in the availability and consumption of antibiotics. In countries with a long tradition
of surveillance programmes such as Australia, Slovakia and Sweden, there have been reductions
in the prescription and use of antibiotics [48]. In our study, ESBL-rate E.coli decreased with
decreased antibiotic consumption in 2010 vs. 2014; however, this was still high at 28% in 2014 .
For an antibiotic to be considered as first line empirical treatment for urinary tract infections,
resistance should not exceed 20% in the most likely infecting strains [49, 50]. According to these
criteria, all third generation cephalosporins used in our hospital are currently above this with
reported resistance rates from 25-28% (Figure 5). The use of antimicrobials for which the
with pyelonephritis. Consequently, in this situation, healthcare providers should consider empiric
treatment with carbapenem or amikacin or another agent found to be consistently active on the
basis of the local antibiogram. This policy has again already been introduced into our hospital,
and again we will be monitoring the situation to provide guidance to others.
Encouragingly, the rate of MRSA among the pediatric population in KC Kragujevac is relatively
low compared to reports from other countries [52], and it should be kept this way through the
continuous monitoring of local S. aureus susceptibility patterns.
Since cloxacillin must be administered frequently (i.e. four times daily in children), and
cloxacillin is sometimes associated with severe phlebitis, cefazoline is a reasonable substitute for
the empiric management of bacteremia with MSSA. With such high levels of resistance in our
hospital, clindamycin should only be used for infections caused by MSSA if the sensitivity of an
isolate was confirmed, and the D-test for erythromycin
–
induced resistance was negative. Such
recommendations have also now been in introduced in our hospital.
As can be seen (Section 3.3 as well as Tables 1S and 2S), the costs of antibiotics have been
falling in recent years. This can be partially explained by a reform in the procurement system for
hospital medicines in Serbia. Until 2013, Serbia had a system whereby each hospital procured
their own medicines individually, choosing their own suppliers and brands for medicines to
address particular diseases. Rather than competing on price, suppliers typically competed on the
level of “rebate” offered to a hospital to increase the monies available to the hospita
l to purchase
other goods and services. These rebates were often as much as one-third of the total purchase
price. The new procurement system was introduced in 2014 to address this leading to central
procurement and an appreciable drop in prices such as prices for ceftriaxone [32] (Table 1).
We acknowledge that there are typically a low number of tissue specimens analyzed in Serbian
hospital, which may have influenced interpretation of the results. General limitations of DDDs
are common for all aggregated data, exacerbated in the case of paediatric patients. This together
with and the limitations of the aggregate microbiology data are described by Goryachkina et al.
[26]. Calculations of costs and drug utilization in children based on adult DDDs can also not be
used for estimates of prevalence, so the only aspects we could follow were time trends and
comparisons between the groups. Despite these limitations, we believe our findings are robust
and are already influencing prescribing in this hospital and wider.
CONCLUSIONS AND RECOMMENDATIONS
Overall, we believe our findings show that increased local efforts to enhance surveillance for
AMR are necessary to inform treatment decisions, especially empiric use. The approach to local
infection control should be multifaceted and should include microbiology and utilization
assessments together with measures to improve local hygiene such as improved hand-hygiene in
wards [53-56]. The development of pro-active antibiotic stewardship programs is a way forward
[13-15,29,57-61] as well as consulting microbiologists and clinical pharmacologists when
prescribing antibiotics for complex clinical cases [62]. Furthermore, joint efforts should be made
to enhance appropriate antibiotic prescribing and dispensing in all primary, secondary and
tertiary care settings in Serbia which treat children. This again will be the subject of future
research projects together with increasing efforts in Serbia to reduce the illegal purchase of
antibiotics in Serbia [37] as well as improve physician education surrounding antibiotic use.
Finally, we hope this original research in Serbia has implications for other central and eastern
European countries struggling to enhance their appropriate use of antibiotics.
Acknowledgements.
All authors have been active participants in the research. We would like to thank Mr Radovan
Kuzmanovic for IT support regarding microbial resistance data.
Funding and Conflicts of interest
There was no external funding for this research and no conflicts of interest. However, the
write-up of the paper was in part swrite-upported by a grant from the Karolinska
No author has conflicts of interest to declare.
Key points
The appropriate use of antibiotics especially in children is of growing importance given the
extent of antibiotic resistance across countries including Serbia and the lack of new
antibiotics
Knowledge of current antibiotic utilisation patterns coupled with knowledge regarding
current resistance rates is essential to improve the empiric use of antibiotics and reduce future
AMR rates across sectors including hospitals
Effective antibiotic guidance can be developed by combining an analysis of antibiotic
utilisation and resistance patterns even in countries with limited resources, and lead to
changes in the future empiric use of antibiotics and subsequent changes in resistance rates
Reserving antibiotics through formal guidelines can help control their use, especially if prior
authorisation schemes are in place in hospitals. However, this needs to be followed up with
education and other initiatives to improve future use
Appropriate use of antibiotics coupled with changes in pricing policies can appreciably
reduce their costs benefitting all key stakeholder groups
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Good paper outlining the impact of a recent antibiotic stewardshop programme
*14. Hulscher M, Prins JM. Antibiotic stewardship: does it work in hospital practice? A review
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Good paper outlining antibiotic stwardship programmes in practice in hospitals
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for listing/delisting of reimbursement medicines in/from the list of medicines prescribed and
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Good paper outlining a new methodology to review utilisation patterns alongside resistance
patterns to guide future care
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Landmark paper in Serbia discussing antibiotic use in this important patient population
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29. Pulcini C. Antibiotic stewardship: update and perspectives. Clinical Microbiology and
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30. Araujo da Silva AR, Albernaz de Almeida Dias DC, Marques AF, Biscaia di Biase C, Murni
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losartan utilization post generics: impact and implications. Front Pharmacol 2014;5:219
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Interesting paper discussing prescribing and resistance patterns in ambulatory care
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Landmark paper in this population to provide guidance on future care
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Well conducted research discussing empiric use of ceftriaxone in this patient population
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57. Viale P, Tumietto F, Giannella M, et al. Impact of a hospital-wide multifaceted programme
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58. Rocha-Pereira N, Lafferty N, Nathwani D. Educating healthcare professionals in
antimicrobial stewardship: can online-learning solutions help? J Antimicrob Chemother
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59. Zhang YZ, Singh S. Antibiotic stewardship programmes in intensive care units: Why, how,
and where are they leading us. World J Crit Care Med 2015;4:13-28.
60. Pollack LA, Srinivasan A. Core elements of hospital antibiotic stewardship programs from
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